Irritable Bowel Syndrome (IBS) is a stress-related disorder characterized by colon hypermotility and anxiety. Significant evidence implicates corticotropin-releasing hormone (CRH) in both the colonic dysfunctions and anxiety associated with ISB. Although the site at which CRH acts to produce these effects is unknown, the major brain noradrenergic nucleus, locus coeruleus (LC), is one potential target because the LC is activated by both CRH and colonic distention, and LC activation has been implicated in anxiety. Our preliminary studies suggest that central CRH mediates LC activation by colon distention. Others have shown that central CRH increases distal colon motility. Parallel activation of the LC noradrenergic system and colon motility by CRH could coordinate the cognitive and visceral symptoms of IBS. To begin to elucidate the role of CRH/LC interactions in IBS, the proposed studies will test the hypotheses that 1) CRH acting as a neurotransmitter in the LC mediates its activation by colon distention (AIM 1); 2) Prior stress (which has been implicated in IBS) sensitizes LC neurons to colon distention (AIM 2); and 3) The CRH afferents involved in LC activation by colon distention originate from Barrington's nucleus, a pontine nucleus which projects to the sacral parasympathetic nucleus that innervates the pelvic viscera (AIM 3). Together, these studies have implications for understanding the etiology of IBS, as well as understanding the integration between the brain and visceral function.